Is being the first ever ‘better' than being the best?

For any pharmaceutical organisation, deciding which direction to take their R&D pipeline in is a crucial but incredibly tough decision. All of us have family or friends who use drugs to treat a wide array of medical conditions, from cardiovascular disease to cancer. However, a miniscule percentage of us have been faced with the choice of what to invest in. The choice itself is not easy and there is no obvious ‘right' answer. Every organisation, even the biggest pharmaceutical company, has limited resources and therefore they must determine which ideas to run with and which they deem to be too risky or without sufficient benefit. This can be extremely hard to judge at the onset when the clinical outcome will only be known years down the line. So how do these key decision makers choose?

A major step in this decision making process is establishing which class the R&D program should fall into. The two main categories discussed are best-in-class and first-in-class [1]. Yes – best-in-class drugs sound like the ‘better' option. They have a clinical advantage over what is currently available on the market for a given indication and the mechanism of action has already been proven to be effective in patients. However, although it has been successful in many cases, there are no guarantees that a best-in-class program will produce a drug that is superior to its competitors in what, in some cases, is an already crowded market.

First-in-class drugs, on the other hand, have a different appeal. The FDA defines a first-in-class drug as one that ‘uses a novel and unique mechanism of action to treat a medical condition', therefore they are innovative, cutting-edge, and have the potential to produce unprecedented patient outcomes [2]. Obviously, as is the case with most things that are new and pioneering, there are unavoidable risks that must be considered. A mechanism of action may have been identified that should work theoretically to give a specific result but no compounds show sufficient efficacy. Even if there are compounds that show promise in the early stages, moving into animals and humans is another matter. Finally, even if an effective and safe drug is eventually developed, it must out-perform the drugs already available.

Despite these risks, first-in-class drugs combat the lack of innovation in the pharmaceutical industry that the media often pick up on. With several blockbuster drugs losing patent protection in the recent past and more coming off-patent in the coming few years, this is an extremely important time for new compounds to enter the market. From a financial point of view, focusing on first-in-class drugs may be a way for big pharma as well as biotechs to boost their pipelines and steal market share from competitors investing in the same therapy area.

In order to celebrate the potential of first-in-class drugs and recognise how important they are to the pharmaceutical and healthcare industry, they are the focus of the first ever cross-series themed issue in the Expert Collection (the Expert Opinion and Expert Reviews series') has put together the first cross-series themed issue on first-in-class drugs. This special issue includes 20 articles published between January and April 2014 across 12 journals and covers a wide range of drugs and therapeutic areas.

One article in Expert Review of Clinical Pharmacology describes the safety profile of recombinant adeno-associated viral vectors with a specific focus on the first-in-class drug, alipogene tiparvovec. Florence Salmon, Konstantina Grosios and Harald Petry discuss acute reactions, immunological reactions to the AAV capsid and expressed transgene, viral biodistribution and shedding, DNA integration and carcinogenicity. Jay Wofford and Alan Menter describe the clinical efficacy ustekinumab and explain where it fits within the psoriatic arthritis market in their Expert Review of Clinical Immunology drug profile.

In Expert Opinion on Pharmacotherapy, Tarik Asselah evaluates Gilead's sofosbuvir for the treatment of hepatitis C virus and comments on the favourable safety profile and combination therapies. Editor-in-Chief of Expert Opinion on Pharmacotherapy, Dimitri Mikhailidis (University College London) commented; ‘There is no doubt that we need more new drugs to treat diseases. The first-in-class drugs pave the way for further improvements. It follows that any article describing such a drug will be of interest to those managing patients who may benefit from such treatment’.

Martin Braddock shares his opinion on a novel PcrV antibody which has received an orphan drug designation for the treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis in Expert Opinion on Orphan Drugs. He addresses the challenges associated with targeting this infection and discusses the merits and disappointments from the early clinical data. Ian Phillips (Keck Graduate Institute of Applied Life Sciences), the Editor-in-Chief of Expert Opinion on Orphan Drugs, explained; ‘At a time when the pipeline for new drugs seemed to be drying up because the pool of patents for major drugs is expiring, along comes an increase of first-in-class drugs. There will be followers – the ‘me-too' drugs - based on using the same idea with enough variation on the theme to be similar but different. The owner of a first-in-class drug usually gets an advantage. The brand name becomes associated with a new class of drugs and when there is no better drug for a disease, it may rule in the absence of competitive alternatives’.

The special issue also features a drug discovery case history about perampanel for epilepsy by Takahisa Hanada. The Expert Opinion on Drug Discovery author describes the process Eisai went through to identify and test perampanel before providing his expert opinion on the clinical data. David R Janero (Northeastern University), the Editor-in-Chief of Expert Opinion on Drug Discovery provided his thoughts; ‘In these times of economic distress and limited professional opportunities for scientists involved in discovery R&D, a best-in-class fast-follower with minimal structural variation from and functional/pharmacological correspondence to a first-in-class drug may represent the most attractive combination of target/mechanism de-risking and potential for healthy market share and return on investment’.

In one of the Expert Opinion on Biological Therapy articles in the issue on remestemcel-L for the treatment of acute graft-versus-host disease, George L Chen, Pamela Paplham and Philip L McCarthy added fantastically clear and helpful tables to their article, including one summarising the relevant clinical trials. Editor-in-Chief of Expert Opinion on Biological Therapy, Michael Morse (Duke University Medical Centre), gave his opinion; ‘For me as a clinical/translational researcher in the field of cancer, the appeal of a first-in-class drug is the idea of bringing a new therapy, with hopes for greater efficacy and possibly lower toxicity, to my patients with difficult-to-treat malignancies, especially where there is a substantial unmet need. In immunotherapy, the first-in-class drug with the greatest interest is the anti-PD-1 antibody nivolumab.’

First-in-class drugs are not just of interest to the small number of key decision makers. They are exciting and relevant to healthcare professionals, academic researchers, and pharmaceutical scientists alike. Whether it's studying a new mechanism of action, screening novel compounds, working on pioneering clinical trials or even just learning about ground-breaking medical developments, first-in-class drugs have an appeal that best-in-class drugs do not. This makes them very unique and is the reason why they are the subject of the first Expert Collection cross-series themed issue.